VDAC forms the main interface between mitochondrial and cellular metabolisms by mediating the fluxes of ions, nucleotides and other metabolites across the outer mitochondrial membrane (OMM) (Shoshan-Barmatz, V et al. 2010. Molecular Aspects of Medicine 31(3), 227-286; Shoshan-Barmatz V and Ben-Hail D. 2012. Mitochondrion, 12(1):24-34). VDAC has also been recognized as a key protein in mitochondria-mediated apoptosis. VDAC mediates the release of apoptosis-inducing proteins from mitochondria to the cytosol and regulates apoptosis via interaction with pro- and anti-apoptotic proteins (Shoshan-Barmatz V et al. 2010, ibid; Shoshan-Barmatz V and Golan M. 2012. Current Medicinal Chemistry 19(5), 714-735).
Mitochondrial-bound hexokinase (HK), subtypes I and II (HK-I and HK-II), functions in the coupling of cytosolic glycolysis to mitochondrial oxidative phosphorylation. This is mediated via HK interaction with VDAC1. VDAC1-bound HK also prevents the release of pro-apoptotic factors, and subsequent apoptosis accompanied with detachment of HK. HK detachment from mitochondria has been observed in several pathological conditions, such as Alzheimer's Disease (Saraiva, L M et al. 2010. PLoS ONE 5, e15230), Parkinson's disease (Okatsu, K et al. 2012. Biochem Biophys Res Commun 428, 197-202) and mood and psychotic disorders, including schizophrenia (Rezin G T et al., 2009. Neurochem Res 34, 1021-1029; Regenold, W T ET AL., 2012. J. Psychiatr Res. 46, 95-104; Shan, D et al. 2014. Schizophr Res 154, 1-13).
Piperazine and piperidine are used as essential sub-structure motifs in various drugs. Piperazine pyrrolidine-2,5-dione derivatives have also been demonstrated as malic enzyme inhibitors (Zhang Y J et al. 2006. Bioorganic & Medicinal Chemistry Letters 16, 525-528).
A publication of the inventors of the present invention and co-workers, published after the priority date of the present invention, describes compounds that directly interact with VDAC1 and prevent VDAC1 oligomerization, concomitant with an inhibition of apoptosis as induced by various means and in various cell lines. The compounds protected against apoptosis-associated mitochondrial dysfunction, restoring dissipated mitochondrial membrane potential, and thus cell energy and metabolism, decreasing reactive oxidative species production, and preventing detachment of hexokinase bound to mitochondria and disruption of intracellular Ca2+ levels (Ben Hail D et al., 2016. J Biol Chem 291(48), 24986-25003).
Central nervous system (CNS) disorders are diseases that can affect the brain or spinal cord. The CNS disorders may be caused by trauma, infections, degeneration, structural defects, tumors, blood flow disruption, autoimmunity, or strokes. There exists a wide range of treatments for these disorders, such as surgery, rehabilitation, and medications. Examples of CNS medications include analgesics, anticonvulsants, antipsychotics, sedatives, and tranquilizers. Despite their beneficial effects, CNS medications have the potential for developing tolerance, dependence, or addiction. Psychiatric disorders, including mood disorders and schizophrenia, as well as neurodegenerative disease, are devastating CNS associated diseases with no effective, side-effect free treatment.
Thus, there remains a need for improved treatments of CNS disorders, particularly psychiatric disorders and neurodegenerative diseases that provide increased efficacy and reduces or eliminates any potential side effects.